`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________
`SAMSUNG BIOEPIS CO., LTD.
`Petitioner,
`v.
`REGENERON PHARMACEUTICALS, INC.
`Patent Owner.
`
`Patent No. 11,253,572
`
`_______________
`Inter Partes Review No. IPR2023-00884
`____________________________________________________________
`
`DECLARATION OF MICHAEL W. STEWART, M.D.
`
`
`
`
`
`
`
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2065 Page 1
`
`

`

`TABLE OF CONTENTS
`
`
`Page
`
`
`INTRODUCTION .......................................................................................... 1 
`I.
`SUMMARY OF OPINIONS .......................................................................... 1 
`II.
`III. QUALIFICATIONS ....................................................................................... 3 
`IV. MATERIALS CONSIDERED ....................................................................... 5 
`V.
`LEGAL STANDARDS .................................................................................. 5 
`VI. TECHNICAL BACKGROUND .................................................................... 8 
`A. Angiogenic eye disorders ..................................................................... 8 
`B.
`Prior art therapies for angiogenic eye disorders ................................. 11 
`C.
`Eylea ................................................................................................... 17 
`VII. THE ’572 PATENT ...................................................................................... 19 
`VIII. PETITIONER’S PRIOR ART REFERENCES ........................................... 20 
`A.
`2009 Press Release (Ex.1005) ............................................................ 21 
`B. Dixon (Ex.1009) ................................................................................. 21 
`C. Hecht (Ex.1016) ................................................................................. 24 
`D.
`Shams (Ex.1017) ................................................................................ 25 
`E.
`Elman 2010 (Ex. 1018) ...................................................................... 26 
`F.
`2006 Press Release (Ex.1027) ............................................................ 27 
`G.
`2007 ARVO Abstract (Ex.1030) ........................................................ 28 
`H.
`Randolph (Ex. 1032) .......................................................................... 28 
`I.
`Fraser (Ex. 1033) ................................................................................ 29 
`IX. PERSON OF ORDINARY SKILL IN THE ART ....................................... 29 
`X.
`CLAIM CONSTRUCTION ......................................................................... 30 
`A.
`results limitations ............................................................................... 30 
`B.
`“approximately 4 weeks following the immediately preceding
`dose . . . approximately 8 weeks following the immediately
`preceding dose” .................................................................................. 30 
`XI. ANALYSIS OF PRIOR ART ....................................................................... 36 
`
`
`
`-i-
`
`
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2065 Page 2
`
`

`

`TABLE OF CONTENTS
`(continued)
`
`Page
`
`-ii-
`
`
`
`The prior art does not disclose or suggest the required benefits
`to visual acuity for angiogenic eye disorders, in general, or for
`AMD, specifically .............................................................................. 36 
`1.
`In general, partial results from Phase I and II clinical
`trials do not predict a Phase III clinical trial’s outcome .......... 37 
`No POSA would have reasonably expected the 2q8
`regimen to succeed based on Dixon and the 2006 Press
`Release ..................................................................................... 38 
`a.
`Claim 1 ........................................................................... 39 
`b.
`Claims 2, 3, 8, and 10 .................................................... 42 
`c.
`Claims 4 and 9 ............................................................... 42 
`d.
`Claims 5 and 11 ............................................................. 43 
`e.
`Claims 26-28 .................................................................. 43 
`f.
`Claims 29 and 30 ........................................................... 46 
`The prior art does not disclose or suggest the required benefits
`to visual acuity in the context of DME .............................................. 47 
`It was not obvious to formulate aflibercept as an isotonic
`solution or with a non-ionic surfactant ............................................... 49 
`1.
`Neither Dixon nor Hecht renders obvious an isotonic
`solution ..................................................................................... 49 
`Neither Dixon nor Hecht renders obvious a non-ionic
`surfactant .................................................................................. 50 
`D. Using exactly four secondary doses was not obvious from the
`2009 Press Release, Shams, and Elman 2010 .................................... 53 
`1.
`The 2009 Press Release does not teach or suggest the
`dosing regimen of claim 25 ...................................................... 54 
`The 2009 Press Release in combination with Shams does
`not teach or suggest the dosing regimen of claim 25 ............... 56 
`a.
`Shams does not teach or suggest more loading
`doses............................................................................... 56 
`
`2.
`
`2.
`
`2.
`
`A.
`
`B.
`
`C.
`
`
`
`
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2065 Page 3
`
`

`

`TABLE OF CONTENTS
`(continued)
`
`Page
`
`
`
`b.
`
`c.
`
`d.
`
`Shams and the 2009 Press Release do not narrow
`down the numerous ways to modify the DA VINCI
`2q8 dosing regimen ....................................................... 59 
`A POSA would not arrive at the claimed regimen
`with “routine optimization” or “routine
`adjustments” .................................................................. 60 
`A POSA would not have a reasonable expectation
`of success in using a fixed extended dosing
`regimen in order to treat effectively while
`minimizing the number of loading doses ...................... 63 
`The 2009 Press Release in combination with Elman 2010
`does not teach or suggest the dosing regimen of claim 25 ...... 66 
`a.
`Elman teaches monthly doses based on individual
`patient assessments ........................................................ 66 
`Elman does not teach using exactly five loading
`doses............................................................................... 68 
`Elman’s results do not show any benefit of five
`loading doses ................................................................. 72 
`There is no motivation to combine Elman 2010
`with the 2009 Press Release .......................................... 75 
`XII. COMMERCIAL SUCCESS ......................................................................... 85 
`A. Nexus to Eylea .................................................................................... 85 
`B.
`Commercial success of Eylea ............................................................. 91 
`XIII. EXHIBITS 2109 & 2112-2114 ..................................................................... 91 
`
`
`
`3.
`
`b.
`
`c.
`
`d.
`
`
`
`-iii-
`
`
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2065 Page 4
`
`

`

`
`
`I, Michael W. Stewart, M.D., make this declaration in connection with the
`
`proceeding identified above.
`
`I.
`
`INTRODUCTION
`
`1.
`
`I have been retained by counsel for Patent Owner, Regeneron
`
`Pharmaceuticals, Inc., (“Regeneron”) as a technical expert in connection with the
`
`proceeding identified above. I submit this declaration in support of Patent Owner’s
`
`Response in connection with the Inter Partes Review of United States Patent
`
`No. 11,253,572 (“the ’572 Patent”).
`
`2.
`
`I am being paid at my usual hourly rate for my work on this matter. I
`
`have no personal or financial stake or interest in the outcome of the present
`
`proceeding.
`
`II.
`
`SUMMARY OF OPINIONS
`
`3.
`
`It is my opinion that the challenged claims of the ’572 Patent are
`
`nonobvious and patentable. The following is a summary of my opinions:
`
` The results of the recited dosing regimens for angiogenic eye disorders,
`
`in general, and for age related macular degeneration, specifically, were
`
`not obvious over Dixon, either alone or in view of the 2006 Press
`
`Release.
`
`
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2065 Page 5
`
`

`

`IPR2023-00884
`
`
` The results of the recited dosing regimen for diabetic macular edema
`
`
`
`were not obvious over the 2009 Press Release, either alone or in
`
`combination with the 2007 ARVO Abstract and/or Dixon.
`
` Formulating aflibercept in an isotonic solution or with a non-ionic
`
`surfactant was not obvious over Dixon, either alone or in combination
`
`with Hecht.
`
` Using exactly four secondary doses was not obvious over the 2009
`
`Press Release, either alone or in combination with Shams and Elman
`
`2010.
`
` Eylea embodies the claims of the ’572 Patent such that there is a nexus
`
`between the ’572 Patent and the commercial success of Eylea.
`
` I further am aware that Regeneron contends that the November 2010
`
`Press Release (Ex.1007), the December 2010 Press Release (Ex.1006),
`
`and ARVO 2010 (Ex.1010) are not prior art to the challenged claims
`
`and thus I understand that Regeneron contends that challenges based on
`
`those references also do not establish obviousness. I offer no opinions
`
`regarding those references.
`
`
`
`2
`
`
`
`
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2065 Page 6
`
`

`

`IPR2023-00884
`
`III. QUALIFICATIONS
`
`
`
`4.
`
`I am the Chair of the Department of Ophthalmology at Mayo Clinic in
`
`Jacksonville, Florida, where I have been Chair since 2005 and Consultant since
`
`2002. I have been a Professor of Ophthalmology at the Mayo Clinic College of
`
`Medicine and Science since 2014 and am currently the Knights Templar Eye
`
`Foundation, Inc. Professor of Ophthalmology Research.
`
`5.
`
`I graduated from Harvard University with a degree in Chemistry
`
`cum laude in 1979. I received my M.D. at McGill University School of Medicine in
`
`1983. I completed fellowships at the Retina Research Foundation and University of
`
`California, Davis, in Vitreoretinal Diseases from 1987 to 1989.
`
`6.
`
`I have been a Councilor of the American Academy of Ophthalmology;
`
`Chief of Ophthalmology at St. Luke’s Hospital at Mayo Clinic during 2002-2008;
`
`Executive or Associate Editor at the American Journal of Ophthalmology since
`
`2013; President or Vice President of the Florida Society of Ophthalmology during
`
`2004-2005; and President of Duval County Ophthalmology Society during 1992-
`
`1994. I am the current President of the International Joint Commission of Allied
`
`Health Personnel in Ophthalmology, and I have served in numerous additional
`
`leadership roles in professional organizations and societies in the ophthalmology
`
`field over the past three decades. I have also been a peer reviewer for more than 130
`
`
`
`3
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2065 Page 7
`
`

`

`IPR2023-00884
`
`journals in the field, including Retina, Ophthalmology, and the British Journal of
`
`
`
`Ophthalmology.
`
`7.
`
`I maintain an active medical and surgical practice and have been
`
`continuously elected as one of “America’s Best Physicians” since 2016. My honors
`
`include the American Academy of Ophthalmology Honor Award (2010); Hiram
`
`Hunn Award from Harvard University (2012); American Society of Retina
`
`Specialists Honor Award (2016); Marquis Who’s Who in America (2018); and
`
`President’s Award from the Florida Society of Ophthalmology (2020–2021).
`
`8.
`
`I have written and published over 600 national and international
`
`meeting presentation, abstracts, book chapters, and scientific papers including many
`
`of the primary papers on treatment of diabetic retinopathy and diabetic macular
`
`edema, using anti-vascular endothelial growth factor (“anti-VEGF”) therapies,
`
`especially intravitreal aflibercept.
`
`9.
`
`I have extensive experience as a Principal Investigator on a number of
`
`clinical trials, including clinical trials of anti-VEGF agents, such as aflibercept
`
`(Regeneron’s Eylea), in age-related macular degeneration and macular edema
`
`following central retinal vein occlusions. For example, I was a lead investigator on
`
`Regeneron’s Phase III studies of the efficacy, safety, and tolerability of repeated
`
`doses of intravitreal VEGF Trap in subjects with neovascular age-related macular
`
`
`
`4
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2065 Page 8
`
`

`

`IPR2023-00884
`
`degeneration (VIEW1 and VIEW 2), as well as Regeneron’s Investigation of
`
`
`
`Efficacy and Safety in Central Retinal Vein Occlusion (“CRVO”) (GALILEO).
`
`10. A current copy of my curriculum vitae is filed herewith as Ex.2096.
`
`IV. MATERIALS CONSIDERED
`
`11.
`
`In preparing this declaration, I have reviewed, among other things, the
`
`following materials:
`
`a.
`
`b.
`
`the Petition for Inter Partes Review of the ’572 Patent, Paper 1
`(“Petition”);
`the Declaration of Dr. Edward Chaum, Ex.1002 (“Chaum
`Declaration”);
`the Board’s Decision Granting Institution of Inter Partes
`Review, Paper 13; and
`d.
`all exhibits cited in this declaration.
`V. LEGAL STANDARDS
`
`c.
`
`12.
`
`I have been informed that claim terms are given their plain and ordinary
`
`meaning as understood by a so-called “Person of Ordinary Skill in the Art,” or
`
`“POSA” at the time of the invention. I understand that the most relevant information
`
`for construing claims is the intrinsic record of the patent. The intrinsic record
`
`includes the specification, prosecution history, claims, and related patents. If this
`
`record is inconclusive, I understand that extrinsic evidence, such as dictionary
`
`definitions and trade usage, may be used to inform the meaning of a term.
`
`
`
`5
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2065 Page 9
`
`

`

`IPR2023-00884
`
`
`
`
`13.
`
`I have been informed that the obviousness of an invention is considered
`
`from the perspective of a POSA as of the priority date of the patent. The POSA is a
`
`hypothetical person who is presumed to have understood the state of the art in the
`
`field of the claimed invention and who can apply that understanding with ordinary
`
`creativity. I have been asked to assume that the priority date of the ’572 Patent is
`
`January 13, 2011. I have therefore considered the art from the perspective of a POSA
`
`as of January 13, 2011. I understand that Petitioner has applied a priority date of
`
`July 12, 2013. My conclusions would be the same if I were to consider the art from
`
`the perspective of a POSA as of July 12, 2013.
`
`14.
`
`I have also been informed and understand that the subject matter of a
`
`patent claim is obvious if the differences between the subject matter of the claim and
`
`the prior art are such that the subject matter as a whole would have been obvious at
`
`the time the invention was made to a POSA to which the subject matter pertains. I
`
`have also been informed that the framework for determining obviousness involves
`
`considering the following factors: (i) the scope and content of the prior art; (ii) the
`
`differences between the prior art and the claimed subject matter; (iii) the level of
`
`ordinary skill in the art; and (iv) any objective evidence of non-obviousness. I also
`
`understand that for a POSA to rely on the disclosures of multiple references, there
`
`must be some motivation to combine their respective disclosures. I understand that
`
`the claimed subject matter would have been obvious to a POSA if, for example, it
`6
`
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2065 Page 10
`
`

`

`IPR2023-00884
`
`results from the combination of known elements according to known methods to
`
`
`
`yield predictable results, the simple substitution of one known element for another
`
`to obtain predictable results, or use of a known technique to improve similar devices
`
`in the same way or applying a known technique to a known device ready for
`
`improvement to yield predictable results. I have also been informed that the analysis
`
`of obviousness may include recourse to logic, judgment, and common sense
`
`available to the POSA, and is not limited to statements made in the prior art
`
`references.
`
`15.
`
`I have been informed and understand that a result or solution may be
`
`“obvious to try” when a POSA is choosing from a finite number of identified,
`
`predictable solutions with a reasonable expectation of success. I have also been
`
`informed that, where the prior art only gives general guidance and gives no direction
`
`as to which of many possible choices is likely to be successful, relying on an
`
`obvious-to-try theory is not appropriate. Similarly, I have been informed that a
`
`POSA may arrive at a claimed invention using “routine optimization” within a
`
`limited range disclosed in the prior art.
`
`16.
`
`I have also been informed and understand that whether a prior art
`
`document “teaches away” from a particular path or combination of elements may
`
`inform whether or not the claimed element is obvious. I understand “teaching away”
`
`
`
`7
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2065 Page 11
`
`

`

`IPR2023-00884
`
`to mean that a POSA would be discouraged from following a particular path or
`
`
`
`would be led in a direction divergent from that path.
`
`17.
`
`I have also been informed and understand that when considering
`
`obviousness, the commercial success of a patented product may indicate that the
`
`claims are not obvious. I understand that in order for commercial success to be
`
`considered, there must be a nexus between the claims and the product, meaning the
`
`value of the product is derived from the patented features. I understand that a nexus
`
`can be shown by demonstrating that the commercially successful product or method
`
`embodies or practices the claimed invention.
`
`VI. TECHNICAL BACKGROUND
`
`A. Angiogenic eye disorders
`
`18. Angiogenesis is the process of forming new blood vessels from
`
`preexisting vasculature. It is a complex process comprising multiple steps, illustrated
`
`in Figure 1:
`
`
`
`8
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2065 Page 12
`
`

`

`IPR2023-00884
`
`
`Figure 1: Steps of angiogenesis. Ex.2112, 3.
`
`
`
`
`
`19.
`
`In the first step, an angiogenic “switch” is turned on by a proangiogenic
`
`growth factor, such as vascular endothelial growth factor (“VEGF”). From there,
`
`endothelial cells are stimulated to proliferate. While angiogenesis is a normal part of
`
`development and healing, as with most processes in the body, a balance must be
`
`achieved between production, degradation, and reformation. When there is
`
`imbalance between proangiogenic factors (e.g., VEGF) and antiangiogenic factors,
`
`pathology ensues. Ex.2113, 1. Since newly formed vessels do not yet have fully
`
`formed and functional endothelial and pericyte layers, blood vessel leakage is often
`
`associated with angiogenesis. Vascular leakage and angiogenesis are pathogenic
`
`
`
`9
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2065 Page 13
`
`

`

`IPR2023-00884
`
`findings in many diseases such as diabetic macular edema (“DME”) and wet age-
`
`
`
`related macular degeneration (“AMD”). Ex.2113, 3, Figs.2–3; Ex.2123, 2.
`
`20. DME is a chronic disease in individuals with diabetes as a result of
`
`damage to small blood vessels in the retina. The retina is the multi-layered structure
`
`of light-sensitive and processing cells in the back of the eye that converts light into
`
`electrical signals. In people with diabetes, high blood sugar levels over extended
`
`periods of time can damage the tiny blood vessels within the retina or cause them to
`
`block completely. As a result, tiny bulges called microaneurysms form in the blood
`
`vessels. Fluid may also leak from incompetent blood vessels. This leakage can cause
`
`swelling in the center part of the retina, which is called the macula, resulting in DME.
`
`DME causes diminished central vision and loss of fine detail and is the most
`
`common cause of vision loss among diabetic patients. Ex.2123, 1; Ex.1001, 1:47–
`
`60.
`
`21. Like DME, AMD is a chronic disease mediated by VEGF that causes
`
`diminished central vision and loss of fine detail. Unlike DME, however, AMD is
`
`characterized by deposits of lipid (drusen) beneath the retinal pigment epithelium,
`
`pigmentary alterations in the macula, and thinning of the choroidal circulation
`
`beneath the macula. AMD begins as “dry AMD” and can progress to “wet AMD,”
`
`or “wAMD,” which involves the gradual, abnormal growth of blood vessels from
`
`the choroidal vasculature into the retina. Those vessels leak, spilling fluid into the
`10
`
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2065 Page 14
`
`

`

`IPR2023-00884
`
`macula and thereby causing vision loss. Without treatment, most people with
`
`
`
`wAMD go blind.
`
`B.
`
`Prior art therapies for angiogenic eye disorders
`
`22. Retinal laser therapy has been used to treat angiogenic eye disorders for
`
`over 50 years. One type of laser treatment is focal laser treatment, wherein the laser
`
`treatment is placed within the macula. Another type of laser treatment is scatter laser,
`
`or panretinal photocoagulation, which comprises more extensive laser applied to the
`
`peripheral retina to reduce ischemia.
`
`23. From the 1970s through the 1990s, the Diabetic Retinopathy Study
`
`(DRS) and ETDRS evaluated laser photocoagulation treatment for angiogenic eye
`
`disorders, including DME. Ex.2121; Ex.2122; Ex.2124. It had been recognized early
`
`on that “[h]armful effects of treatment” existed, namely, that laser photocoagulation
`
`caused injury to photoreceptor cells, and this could also lead to vision loss. For some
`
`disorders, it was recommended that “[t]he risk of severe visual loss without
`
`treatment substantially outweighs the risks of photocoagulation … and prompt
`
`treatment is usually advisable.” Ex.2122, 7. On the other hand, “[f]or eyes without
`
`macular edema, neither of the strategies for early photocoagulation … was better
`
`than deferral of photocoagulation for preventing either moderate or severe visual
`
`loss …. Eyes assigned to early full scatter were more likely to have moderate visual
`
`loss during the first 2 years of follow-up than eyes assigned to deferral” Ex.2121,
`11
`
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2065 Page 15
`
`

`

`IPR2023-00884
`
`17 (emphasis added). In other words, while the risk of visual loss due to laser may
`
`
`
`have been balanced for patients at high risk of vision loss due to the underlying
`
`disease, there was “small benefit of early photocoagulation in reducing risk of severe
`
`visual loss” for patients who had not yet reached such an advanced stage. Ex.2121,
`
`19. Focal laser became the gold standard for treating DME. Ex.2125, 1–2; Ex.2126,
`
`1–2.
`
`24. Laser therapies also have been used to treat wAMD. In 1999, the
`
`Treatment of Age-related Macular Degeneration with Photodynamic Therapy (TAP)
`
`Study Group published the results from two clinical trials that treated wAMD with
`
`photodynamic therapy with verteporfin. Ex.2127. The studies’ authors reported that
`
`photodynamic therapy slowed the rate of vision loss in some patients, and from 2000
`
`and 2005, photodynamic therapy was the preferred therapy for patients with
`
`predominantly classic wAMD. Ex.2127, 1. Photocoagulation therapy also had been
`
`used to treat wAMD but can produce harmful side effects, frequently fails, and its
`
`benefits for wAMD were “limited.” Ex.2127, 4.
`
`25. Around the same time as the DRS and TAP groups’ investigations,
`
`researchers were characterizing a family of potent growth factors called VEGFs.
`
`VEGF is a secreted endothelial cell mitogen and angiogenesis factor regulated by
`
`hypoxic
`
`(or
`
`low oxygen) conditions, which are known
`
`to stimulate
`
`neovascularization. Ex.2095, 1; Ex.2114, 3; Ex.2120, 3. VEGF levels are
`12
`
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2065 Page 16
`
`

`

`IPR2023-00884
`
`significantly increased in eyes with DME and wAMD, and blocking VEGF leads to
`
`
`
`a pronounced reduction in retinal neovascularization. Ex.2132, 1–2. VEGF soon
`
`became known as the principal mediator of angiogenic eye disorders.
`
`26. Beginning in 2004, the U.S. FDA approved a series of anti-VEGF
`
`agents. Macugen (pegaptanib) was the first such agent for use in wAMD. Ex.2115.
`
`In the same year, the anti-VEGF monoclonal antibody Avastin (bevacizumab) was
`
`approved for use in advanced solid cancers, and it was soon adopted for off-label
`
`treatment of angiogenic eye disorders. Ex.2107, 2, 7; Ex.2108. Shortly after, in 2006,
`
`the antibody fragment Lucentis (ranibizumab) was approved for treatment of
`
`wAMD. Ex.1034, 2, 5.
`
`27. ANCHOR and MARINA were Genentech’s pivotal trials evaluating
`
`Lucentis. Running from March 2003 to December 2005, the MARINA trial recruited
`
`716 wAMD patients with either minimally classic or occult choroidal
`
`neovascularization. MARINA subjects were randomly assigned to receive 1) 24
`
`monthly intravitreal injections of ranibizumab at a dose of 0.3 mg or 0.5 mg, or 2)
`
`sham injections. The one-year interim results, presented in July 2005, showed that
`
`nearly 95% of study subjects reached the primary endpoint of losing fewer than 15
`
`letters from baseline visual acuity at 12 months. Ex.2118, 4. Furthermore, the two-
`
`year results, which were published in October 2006, showed that subjects were not
`
`merely losing less visual acuity, but in fact they were gaining a mean of +6.5 letters
`13
`
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2065 Page 17
`
`

`

`IPR2023-00884
`
`in the 0.3 mg group and +7.2 letters in the 0.5 mg treatment group, while the sham
`
`
`
`treated subjects were losing a mean of -10.3 letters. Ex.1052, 1.
`
`28. The ANCHOR trial, which ran from May 2003 to September 2006, had
`
`the same primary endpoint of measuring the proportion of patients losing fewer than
`
`15 letters from baseline visual acuity at 12 months. In this study, 423 patients with
`
`predominantly classic choroidal neovascularization in wAMD were enrolled.
`
`Ex.1049, 1. ANCHOR subjects were randomly assigned to receive 1) monthly 0.3
`
`mg or 0.5 mg ranibizumab or 2) photodynamic therapy every 3 months. Similar to
`
`the MARINA trial, interim one-year results showed that between 94% and 96% of
`
`the patients receiving ranibizumab maintained or improved vision. Ex.2118, 2–3. By
`
`two years, the ANCHOR study concluded that subjects treated with ranibizumab had
`
`gained a mean of +8.1 to +10.7 letters, while the comparator arm saw a mean loss
`
`of -9.8 letters. Ex.1049, 1.
`
`29.
`
`In both ANCHOR and MARINA, the exceedingly positive outcomes
`
`for patients treated with ranibizumab resulted in a protocol amendment that allowed
`
`patients in the comparator arm to be offered monthly ranibizumab injections.
`
`Ex.2118, 3, 5.
`
`30. Anti-VEGF drugs were believed to hold potential for the treatment of
`
`other angiogenic disorders, so several clinical trials were conducted to evaluate the
`
`efficacy of Lucentis for treatment of other disorders like DME. The safety and
`14
`
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2065 Page 18
`
`

`

`IPR2023-00884
`
`efficacy of Lucentis was subsequently studied by the developer in more than 9,000
`
`
`
`patients, across eight pivotal and 23 clinical trials. Ex.2116, 3. In 2007, the RISE
`
`and RIDE trials began enrollment to evaluate monthly Lucentis for the treatment of
`
`DME. Ex.2109, 4. The protocol entailed 0.3 mg or 0.5 mg monthly intravitreal
`
`injections of the study drug, with sham injections and deferred laser given to the
`
`control group. The primary endpoint was the percentage of subjects who gained ≥ 15
`
`letters in their Best Corrected Visual Acuity (“BCVA”) Score from baseline at
`
`month 24. Ex.2109, 7–8. A secondary endpoint was percentage of subjects with a
`
`≥ 3-step worsening from baseline in the ETDRS Diabetic Retinopathy Severity
`
`Scale Score (“DRSS”) for eyes at months 24 and 36. Ex.2109, 8. Based on the results
`
`from the pivotal RIDE and RISE Phase III clinical trials, Lucentis was approved for
`
`the treatment of DME in 2015. Ex.2110, 1.
`
`31. The Lucentis label instructs monthly injections for the treatment of
`
`AMD and DME. Ex.2111, 2. There are many reasons that monthly intravitreal
`
`injections are a less-than-ideal dosing regimen, including patient discomfort,
`
`inconvenience, cost, compliance, and risks associated with injections. It was not for
`
`lack of effort that Genentech has not found success with a less-frequent fixed dosing
`
`schedule. In fact, Genentech conducted several large-scale, expensive clinical trials
`
`in an attempt to demonstrate the efficacy of less-frequent dosing. These studies
`
`include SUSTAIN, EXCITE, SAILOR, and PIER. Ex.2119, 8–9. However, each of
`15
`
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2065 Page 19
`
`

`

`IPR2023-00884
`
`these studies failed to demonstrate efficacy on par with that of monthly dosing with
`
`
`
`Lucentis.
`
`32. For example, in the PIER study (2004–2007), wAMD patients in the
`
`treatment groups received ranibizumab every month for three doses, followed by
`
`quarterly doses. Ex.1021, 1. BCVA was measured per ETDRS standards. While
`
`patients experienced gains in visual acuity during the monthly dosing phase, “the
`
`treatment effect declined in the ranibizumab groups during quarterly dosing.”
`
`Ex.1021, 1. In fact, the gains in visual acuity were entirely lost once quarterly dosing
`
`began. Figure 1 from the 1-year report of the PIER study shows that one year after
`
`treatment with ranibizumab, patients were on average left with no better, or in some
`
`cases worse, vision than at the start of the study (loss of -0.2 to -1.6 letters in the
`
`ranibizumab-treated groups). Ex.1021, 5, Fig. 1. Compare this to Figure 2 of the
`
`MARINA study, showing mean change in visual acuity of patients receiving
`
`monthly dosing of ranibizumab throughout the 1-year period, wherein patients
`
`gained and maintained +6.5 to +7.2 letters, and it is clear why the PIER trial was
`
`regarded as “highly disappointing” and a “failure” by the investigators (Ex.2066
`
`¶¶25-26) and members of the retinal field, including myself, as well as why
`
`Genentech would amend the protocol to allow all patients to receive monthly dosing
`
`for the remainder of the two-year study. Ex.2103, 1–2; Ex.2104, 2. The two-year
`
`report notes that “switching to monthly ranibizumab treatment late in year 2
`16
`
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2065 Page 20
`
`

`

`IPR2023-00884
`
`appeared to provide increased VA benefit to patients who had previously been
`
`
`
`treated quarterly.” Ex.2103, 2. The inferiority of quarterly dosing is further
`
`acknowledged on the Lucentis label, which notes that quarterly dosing is “less
`
`effective” and “[c]ompared to continued monthly dosing, dosing every 3 months will
`
`lead to an approximate 5-letter (1-line) loss of visual acuity benefit, on average, over
`
`the following 9 months.” Ex.2102, 1. Because the standard of care (monthly
`
`treatment with Lucentis) provided strong gains in visual acuity, and because
`
`abundant evidence showing that extended dosing regimens did not provide the same
`
`efficacy, extended dosing regimens such as the one tested in PIER were not generally
`
`adopted into clinical practice before the priority date.
`
`C. Eylea
`
`33. Unlike bevacizumab or ranibizumab, Regeneron’s aflibercept (Eylea)
`
`is not an antibody or antibody fragment but rather a fusion protein. A fusion protein
`
`is a chimeric molecule engineered from a receptor targeting a ligand of interest fused
`
`to another protein. Spe